Background and Significance: The pattern of cancer metastasis was initially appreciated by Paget, who proposed the "seed (cancer cell) and soil (organ of metastasis)" hypothesis to explain the observed organ tropism of this phenomenon. In this regard, prostate cancer (CaP) has a strong predilection for bone metastasis with other sites being only rarely involved. However, even once lodged in a distant organ, a cancer cell cannot grow >2mm without the process of angiogenesis. Therefore, since the "seed" is the same in all organs, the "soil" must be different in each organ, in order to permit the metastatic cells to grow. Taken together, these observations form the basis of our Guiding Hypothesis can be stated as: the underlying reason for organ tropism of CaP is an organ specific induction of angiogenesis. For example, CaP cells may interpret abnormal cellular environments such as a metastatic site, differently than a normal cell. While a normal prostate epithelial cell thrives in the prostate microenvironment, it does not in the bone stroma. Conversely, a CaP cell may thrive in both microenvironments but not in that of liver tissue, explaining in part the organ tropism of CaP metastasis. We have recently discovered, that the angiogenic factor VEGF can also be regulated by cell surface contact in CaP. Focal adhesion kinase (FAK), Src, PI3K, Raf and MEK were found to be key effectors in this Ras- independent signaling pathway. This novel cell surface mediated signaling pathway may constitute an important way which malignant cells employ to enhance their angiogenic potential and may explain the organ specificity of CaP metastasis. Because of the potential therapeutic applications that inhibition of this process may have on patients with CaP, we propose to further delineate and dissect the mechanisms underlying VEGF induction by cell surface contact by testing the following Hypotheses: 1) Organ specific VEGF induction is a key determinant of organ tropism of CaP growth and metastasis in animal models; 2) FAK, Src, PI3K, Raf, Rap1 and MEK signaling networks are responsible for organ tropic CaP VEGF induction in vivo, 3) Novel intracellular signaling networks and promoter motifs are responsible for cell surface mediated VEGF induction. To test these hypotheses and additionally to lay the ground work for translational connections to human disease, we propose studies with the following Specific Aims: 1) Determine if VEGF induction in metastatic CaP cells is organ specific and whether VEGF is a mediator of organ tropism of CaP metastasis in animal models; 2) Determine the complexity of FAK, Src, PI3K, Raf, Rap1 and MEK signaling networks and their relevance in either organ specific VEGF induction in vivo or organ tropism of metastasis; 3) Discover novel intracellular signaling networks and promoter motifs responsible for cell surface mediated VEGF induction. Conclusions: Successful completion of these specific aims will provide biologically relevant molecular information on the signaling pathways regulating VEGF induction and may both enhance our understanding of the organ specificity of prostate tumor metastasis and provide a foundation for the much-needed development of novel therapies that interfere with this process in patients with this lethal and far too prevalent disease.